Galanin in Alzheimer's Disease

甘丙肽在阿尔茨海默病中的作用

基本信息

批准号：
7619452
负责人：
ELLIOTT Jay MUFSON
金额：
$ 42.53万
依托单位：
RUSH UNIVERSITY MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
1991
资助国家：
美国
起止时间：
1991-09-29 至 2012-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7619452
关键词：
Acetylcholine Affect Agonist Alzheimer&apos s Disease American Amyloid Amyloid deposition Animals Apoptotic Applications Grants Attenuated Binding Biological Assay Biology Brain Brain Injuries Cell Culture Techniques Cell Death Chemicals DSP 4 Data Dementia Deposition Development Disease Elderly Enzyme-Linked Immunosorbent Assay Fiber Figs - dietary GALR2 gene Galanin Grant Hippocampus (Brain)Hypertrophy Injury Investigation Knock-out Knockout Mice Lesion Ligands Mediating Methods Molecular Molecular Biology Mus Neurites Neuronal Plasticity Neurons Neuroprotective Agents Neurotoxins Patients Peptides Peripheral Pharmaceutical Preparations Phenotype Play Process Publications Quantitative Evaluations Research Personnel Role Senile Plaques Sensory Short-Term Memory Stream Stroke Suggestion Testing Therapeutic Time Toxic effect Transgenic Mice United States National Institutes of Health Wild Type Mouse age related amyloid pathology attenuation basal forebrain cholinergic neurons base cognitive function galanin (2-11)-amide galanin receptor healthy aging in vivo insight meetings mouse model nerve supply neuronal survival neuroprotection neurotoxic neurotoxicity new therapeutic target novel programs research study response transgenic model of alzheimer disease

Acetylcholine Affect Agonist Alzheimer&apos s Disease American Amyloid Amyloid deposition Animals Apoptotic Applications Grants Attenuated Binding Biological Assay Biology Brain Brain Injuries Cell Culture Techniques Cell Death Chemicals DSP 4 Data Dementia Deposition Development Disease Elderly Enzyme-Linked Immunosorbent Assay Fiber Figs - dietary GALR2 gene Galanin Grant Hippocampus (Brain)Hypertrophy Injury Investigation Knock-out Knockout Mice Lesion Ligands Mediating Methods Molecular Molecular Biology Mus Neurites Neuronal Plasticity Neurons Neuroprotective Agents Neurotoxins Patients Peptides Peripheral Pharmaceutical Preparations Phenotype Play Process Publications Quantitative Evaluations Research Personnel Role Senile Plaques Sensory Short-Term Memory Stream Stroke Suggestion Testing Therapeutic Time Toxic effect Transgenic Mice United States National Institutes of Health Wild Type Mouse age related amyloid pathology attenuation basal forebrain cholinergic neurons base cognitive function galanin (2-11)-amide galanin receptor healthy aging in vivo insight meetings mouse model nerve supply neuronal survival neuroprotection neurotoxic neurotoxicity new therapeutic target novel programs research study response transgenic model of alzheimer disease

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项目摘要

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) affects more than 4 million Americans, is a major impediment to healthy aging, and is the most common cause of dementia in the elderly. In this competing continuation we will focus on understanding the molecular interactions between the well-defined galanin (GAL) plasticity response seen in Alzheimer's disease, the role that amyloid pathology plays in the initiation of this action and the novel finding that GAL attenuates neuronal amyloid toxicity. Overall, the data presented in this application suggest that amyloid dependent GAL over expression is an endogenous auto neuroprotective mechanism by the brain to minimize amyloid induced toxicity in Alzheimer's disease. Although evidence suggests that GAL has neuroprotective effects in response to brain damage, its response to amyloid is poorly understood. We present for the first time data demonstrating in a well characterized mouse model of AD (APPswe/PSlAE9 mice) that amyloid deposition induces hippocampal GAL hypertrophic neurites; that a loss of GAL fiber innervation in the hippocampus results in an increase in hippocampal amyloid load; that greater Afi (1-42) induced cell death is observed in hippocampal organotypic cultures from GAL knock-out (KO) as compared to wild type (WT) mice; GAL is neuroprotective against Afi(1-42) induced toxicity in hippocampal cultures derived from wild-type mice and GAL over-expressing mice (see Preliminary data). These finding support the hypothesis that amyloid triggers GAL plasticity, that GAL alters amyloid plaque deposition and protects against amyloid neurotoxicity. This application tests the following hypotheses: 1 .Amyloid increases GAL fiber hypertrophy; 2. Loss of GAL innervation increases hippocampal amyloid load; and 3. Manipulation of the levels of endogenous GAL, modulates A-IS (1-42) induced hippocampal cell death. The APPswe/PS1AE9 and GAL over-expressing transgenic mice will be crossed and the hippocampal/cortical amyloid phenotype examined. The proposed investigations are timely as anti-amyloidogenic agents are being developed for Alzheimer's disease. The development of novel pharmacologic therapeutics based directly upon the pathogenics of Alzheimer's disease meet a major unmet need in the field of Alzheimer's disease. The proposed studies will provide new insights into the mechanisms underlying GAL plasticity, GAL role in the attenuation of amyloid toxicity and suggest novel therapeutic targets (e.g., GAL ligands) for the reduction of amyloid toxicity in Alzheimer's disease.

描述（由申请人提供）：阿尔茨海默氏病（AD）影响了超过400万美国人，是健康衰老的主要障碍，并且是老年人痴呆症的最常见原因。在这种竞争延续中，我们将重点放在理解阿尔茨海默氏病中明确定义的可塑性反应之间的分子相互作用，淀粉样蛋白病理在开始这种动作中起着这种作用的作用和新颖的发现，即GAL减弱了神经元淀粉样蛋白的毒性。总体而言，本应用中提供的数据表明，淀粉样蛋白依赖性的GAL超过表达是大脑的一种内源性自身神经保护机制，可以最大程度地减少淀粉样蛋白诱导的阿尔茨海默氏病的毒性。尽管有证据表明GAL响应脑损伤具有神经保护作用，但对淀粉样蛋白的反应知之甚少。我们首次提供了在良好的AD的小鼠模型（AppSwe/pslae9小鼠）中证明淀粉样蛋白沉积会诱导海马GAL肥厚的神经突。海马中GAL纤维神经支配的丧失导致海马淀粉样蛋白负荷增加。与野生型（WT）小鼠相比，在来自GAL敲除（KO）的海马器官培养物中观察到更大的AFI（1-42）诱导的细胞死亡。 GAL对AFI（1-42）的神经保护作用（1-42）诱导的毒性在源自野生型小鼠和GAL过表达的小鼠的海马培养物中（请参阅初步数据）。这些发现支持淀粉样蛋白会触发GAL可塑性的假设，即GAL会改变淀粉样蛋白斑块的沉积并预防淀粉样神经毒性。该申请检验以下假设：1。氨基蛋白增加加仑纤维肥大； 2. GAL神经的丧失增加海马淀粉样蛋白负荷；和3。内源性GAL水平的操纵，调节A-IS（1-42）诱导海马细胞死亡。 AppSwe/ps1ae9和GAL过表达的转基因小鼠将被横断，并检查了海马/皮质淀粉样蛋白表型。拟议的研究是及时的，因为正在为阿尔茨海默氏病开发抗淀粉样蛋白原剂。基于阿尔茨海默氏病的病原体的新型药理学治疗剂的发展满足了阿尔茨海默氏病领域的主要未满足需求。拟议的研究将提供有关GAL可塑性的机制，GAL在淀粉样蛋白毒性衰减中的作用的新见解，并提出新的治疗靶标（例如GAL配体），以降低阿尔茨海默氏病中淀粉样蛋白毒性的降低。